P1033: A PHASE 2 STUDY OF THE LSD1 INHIBITOR IMG-7289 (BOMEDEMSTAT) FOR THE TREATMENT OF ESSENTIAL THROMBOCYTHEMIA (ET)
Authors: F. Palandri, D. M. Ross, T. Cochrane, C. Tate, S. W. Lane, S. R. Larsen, A. T. Gerds, A. B. Halpern, J. Shortt, J. M. Rossetti, K. M. Pettit, J. Liang, A. Mead, M. Marchetti, A. Vannucchi, A. Wilson, J. R. Göthert, M. Hanna, A. Jones, J. Peppe, G. Natsoulis, T. McClure, W.-J. Hong, W. S. Stevenson, C. N. Harrison, M. Talpaz, N. Vianelli, H. Y. Rienhoff
Journal: HemaSphere (2022)

Background: Lysine-specific demethylase-1 (LSD1) is critical for the self-renewal malignant stem cells and maturation of megakaryocytes, the cell central to ET pathogenesis. Bomedemstat is an oral LSD1 inhibitor active in mouse models of MPNs including improved survival (Kleppe et al. 2015; Jutzi et al. 2018). IMG-7289-CTP-201 is an ongoing, global, open-label, Phase 2b study of bomedemstat taken QD for 24+ weeks in patients with ET who are resistant/intolerant to at least one standard treatment (NCT04254978). Aims: Key objectives are safety and response, defined as platelet (plt) count ≤400x109/L without thromboses. Exploratory endpoints include durability of response (defined as plt ≤400x109/L for ≥12 wks) symptom improvement (TSS) and reduction of WBCs and mutation burden. Methods: Key eligibility criteria: cytoreduction required, platelet count >450x109/L, haemoglobin (Hb) ≥10 g/dL. The starting dose is 0.6 mg/kg/d and titrated, if needed, to a platelet count of 200-400x109/L. Results: At data cut-off (3Feb'22), 44 patients had enrolled. Median age was 68 (42-92) yrs; of the patients most recently treated with hydroxyurea, 88% met ELN criteria for resistance/ intolerance. The Day 1 mean plt, WBC and Hb values were 825x109/L (457-2220), 8.9x109/L (3.9-30.6), and 13.1 g/dL (9.4-16.5), respectively. Median TSS at baseline was 15 (0-74). Sequencing 261 genes (N=42) identified mutations in JAK2 (45%), CALR (43%), and MPL (5%). Other mutations (e.g., EZH2, ASXL1, SF3B1, TP53) were present in 29%. Median time on treatment is 29 weeks (0-68). For patients treated ≥12 weeks, 91% (31/34) achieved a plt count of ≤400x109/L in a median time of 8.1 weeks. 83% of patients (20/24) treated for >24 weeks achieved a durable response as defined above. Of the 9/30 (30%) patients Day 1 WBC count ≥10x109/L, 89% (8/9) had a WBC count <10x109/L; all maintained a stable hemoglobin (see figures). In patients with baseline TSS ≥10 (29/43), at Week 12 69% (11/16) showed reductions; 38% (6/16) had improvements >10-points. The median baseline TSS score for fatigue was 5 (N=41). At Week 24, the median score for evaluable patients fell to 3 and dropped to a median of 1 at Week 48. At Week 24 (N=14), JAK2 and CALR mutations were equally sensitive: 87% had a decrease in allele frequencies (mean: -29%; [S.D. 5%]; range -3 to -91). No new mutations were found. The most common AEs regardless of causality were dysgeusia (52%), fatigue (34%), constipation (32%), arthralgia (27%), thrombocytopenia (25%), and contusion (21%). Eight patients reported a total of 12 serious AEs (SAE), with two (thrombocytopenia and mouth haemorrhage reported in 1 patient) deemed related per the PI. Seven patients discontinued treatment, 6 due to AEs (fatigue, invasive ductal breast carcinoma, headache, respiratory failure, dysgeusia x 2) and one withdrew consent on Day 1. Similar to an ongoing MF study of bomedemstat (NCT03136185), there have been no safety signals or deaths related to drug. At the censor date, 84% (37/44) of patients remain on study. Image:Summary/Conclusion: To date, in this patient population, bomedemstat is generally well-tolerated, reduces platelets, improves symptoms, reduces the mutation burden, and moderates WBC counts without affecting haemoglobin. For those patients treated for at least 24 weeks, 79% achieved a durable reduction in platelet count to ≤400x109/L without thromboembolic events. A Phase 3 study of bomedemstat for the treatment of ET is being planned.